A strong unmet need exists to develop new treatments for anemias associated with chronic disease states, collectively referred to as anemia of chronic inflammation (ACI). ACI is highly prevalent in the U.S. and makes a large contribution to public morbidity and mortality. Despite billions of dollars spent annually to treat ACI patients, current therapies lack efficacy in many patients and cause potentially serious adverse effects. The mechanism for ACI involves inflammatory cytokines acting to inhibit marrow production of red cells, primarily by two interdependent pathways: (1) blocking iron transfer from macrophages to erythroid precursors (iron restriction) and (2) acting directly on the erythroid precursors to transmit inhibitory signals. Iron restriction potently sensitizes erythroid progenitors to the direct inhibitory effects of the inflammatory cytokines. Clinically, high-dose intravenous iron infusions can ameliorate anemia in ACI patients. We are developing a safe and efficacious therapy to correct anemia in these patients based on our discovery that the aconitase enzyme product, namely isocitrate, functions as a second messenger mediating iron's signal to stimulate erythropoiesis. We established the clinical utility by showing that exogenous isocitrate provided to erythroid progenitors in vitro abrogates the inhibitory effects of iron restriction and restores resistance to inflammatory cytokines. To establish clinical feasibility an commercial potential, we propose to study isocitrate's effects in the principal animal model for ACI, rats with experimentally induced chronic autoimmune arthritis. We aim to demonstrate proof-of-concept for our novel isocitrate technology by: (1) demonstrating isocitrate's curative efficacy in ACI rats using a dosing regimen per intended clinical use; (2) measuring physiological effects of isocitrate therapy on functional biomarkers of erythropoiesis to demonstrate isocitrate is effective; and (3) measuring serum biomarkers and assessing organs at necropsy for signs of systemic toxicity to demonstrate isocitrate is safe. The isocitrate technology was invented at the University of Virginia. The scientific investigators/inventors, in collaboration with Cumberland Pharmaceuticals Inc. and affiliates, are developing isocitrate as a new drug product for intravenous injection or oral dosage form to correct anemia in ACI patients. PUBLIC HEALTH RELEVANCE: Millions of people with lifelong diseases, for example those involving the kidney or cancers also have anemia. Current treatments for this type of anemia (known as anemia of chronic inflammation) are risky, expensive, and ineffective for some patient populations. In the proposed studies, we will study a new drug candidate for anemia of chronic inflammation and demonstrate that it safe and effective in an animal model relevant to the human disease.